Retardation of atherosclerosis in immunocompetent apolipoprotein (apo) E-deficient mice following liver-directed administration of a [E1?, E3?, polymerase?] adenovirus vector containing the elongation factor-1α promoter driving expression of human apoE cDNA

摘要

Although gene transfer of human apolipoprotein E (apoE), a 34-kDa circulating glycoprotein, to the liver of apoE- deficient (apoE-/-) mice using recombinant adenoviral vectors (rAd) is antiatherogenic, its full therapeutic potential has yet to be realized. First generation vectors led to immune clearance of transduced hepatocytes, while an improved vector with adenovirus regions E1, E3 and DNA polymerase deleted also had transient effects due to cellular shutdown of the cytomegalovirus (CMV) promoter. Here, we have studied an alternative promoter from the cellular elongation factor 1α (EF-1α) gene, injecting 6-8 week old apoE-/- mice intravenously with 2x1010 virus particles (vp) of the [E1?, E3?, polymerase?] rAd vector Ad-EF1·-apoE. Plasma apoE levels were low (18-55 ng/ml) and failed to reduce plasma cholesterol or normalize the adverse lipoprotein profile. By contrast, the hyperlipidaemic phenotype of apoE-/- mice treated with Ad-CMV-apoE (2x1010 vp) was transiently normalized. Nevertheless, at termination (265 days) the aortic lesion areas in animals given Ad-EF1·-apoE were significantly reduced by 15% (P<0.05) compared to untreated animals, a decrease approaching that in Ad-CMV-apoE-treated mice (23%; P<0.02). Importantly, the attenuation of apoE transgene expression noted with the CMV promoter was absent with the EF-1α promoter, which gave relatively sustained, albeit low, levels of plasma apoE throughout the study period.